Access N-Difluoromethyl Amide (Peptide) from Carboxylic Acid: A Remodeling Modification of Amide Skeleton

Abstract

Strategies involving N–H functionalization of secondary amide and amide-bond formation have been proven to be ineffective for synthesizing N-CF₂H amides. Subjection of the N-CF₂H carbamoyl fluorides with Grignard reagents was useless to prepare N-CF₂H amide with amino acid at the carbon terminal. The biosynthesis and preparation processes of complex amide molecules often involve organic carboxylic acids. To date, abundant carboxylic acids have not been fully utilized to prepare N-CF₂H amide. Therefore, there is an urgent need to develop new strategies using organic carboxylic acids as starting materials to unlock diverse N-CF₂H amides, especially amino acid-derived amide (peptide) skeleton. Here, we report a general strategy for synthesizing N-CF₂H amide (peptide) from carboxylic acids (amino acids) as starting materials: N-thioformyl amide was prepared through known approaches, then achieving efficient desulfurization-fluorination in the presence of silver(II) fluoride. This racemization/epimerization-free approach provides access to a wide range of different N-CF₂H amides, including amino acid-derived amides (fourteen), polypeptides (three) and drug molecules (nine). Therefore, we propose an N-difluoromethylation modification of complex amide skeleton: preparation of carboxylic acids via amide decomposition or according to mature routes; synthesis of N-thioformyl amide; rapid desulfurization-fluorination.

Keywords

N-Difluoromethyl amide (peptide) / Amide skeleton / Remodeling modification / Amino acid / Rapid desulfurization-fluorination / Silver(II) fluoride

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